The s100 proteins are a family of low molecular weight tissue-specific calcium-binding proteins of modulatory action, which are involved in many physiological processes of the body. The name characterizes the ability of compounds of this group to completely dissolve in a 100% solution of ammonium sulfate at neutral pH values.
Currently, 25 representatives of this family are known, which are characteristic for different tissues. This feature suggests that s100 brain-specific proteins are proteins that are present in brain cells and are involved in neurophysiological processes.
Discovery story
The first s100 protein was isolated in 1965 from the bovine brain by scientists Moore and Gregor. Subsequently, proteins of this family were found in mammals, birds, reptiles and humans. Initially, it was believed that s100 was present only in nervous tissue, but with the development of immunological methods, proteins of this group began to be found in other organs.
General characteristics and topography
Proteins of the s100 family are present only in vertebrates and in humans. 15 of the 25 proteins of this group are brain-specific, most of which are produced by astroglial cells of the central nervous system, but a certain proportion is also present in neurons.
It was found that 90% of the entire s100 fraction in the body is dissolved in the cytoplasm of cells, 0.5% is localized in the nucleus, and 5-7% is associated with membranes. A small portion of the protein is found in the extracellular space, including in the blood and cerebrospinal fluid.
Protein of the s100 group is present in many organs (skin, liver, heart, spleen, etc.), but in the brain it is one hundred thousand times more. The highest concentration is observed in the cerebellum. The s100 protein is also actively produced in melanocytes (skin tumor cells). This has led to the use of this compound as a marker of tissue of ectodermal origin.
Chemically, s100 proteins are dimers with a molecular weight of 10-12 daltons. These proteins are acidic in nature because they contain a large amount (up to 30%) of glutamine and aspartic amino acid residues. S100 molecules do not include phosphates, carbohydrates and lipids. These proteins withstand heat up to 60 degrees.
Structure and spatial conformation
By structure, all members of the s100 family are globular proteins. The composition of one dimeric molecule includes 2 polypeptides (alpha and beta), connected to each other by non-covalent bonds.
Most members of the family are homodimers formed by two identical subunits, but heterodimers are also found. Each polypeptide in the s100 molecule has a calcium binding motif called the EF arm. It is built as a spiral-loop-spiral.
The s100 protein contains 4 α-helical segments, a central hinge region of variable length and two terminal variable domains (N and C).
Action Features
The s100 proteins themselves do not have enzymatic activity. Their functioning is based on the binding of calcium ions, which are involved in many intercellular and intracellular processes, including signaling. The addition of Ca 2 + to the s100 molecule leads to its spatial rearrangement and the discovery of the target protein-binding center, through which interaction with other proteins is carried out.
Thus, s100 does not belong to proteins whose main task is to regulate the concentration of Ca 2 + . Proteins of this group are signal-transforming calcium-dependent biologically active modulators that affect intracellular and extracellular processes through binding to target proteins. Neurotransmitters can also serve as the latter, which is why the influence of s100 on the transmission of nerve impulses is associated.
Currently, it has been revealed that zinc and / or copper ions act as regulators for some s100 instead of Ca 2 + . The addition of the latter can both directly affect the activity of the protein, and change its affinity for calcium.
Functions
A complete picture of the biological role of brain-specific s100 proteins in the body does not yet exist. Nevertheless, the participation of proteins of this group in such processes was revealed:
- regulation of metabolic reactions of nerve tissue;
- DNA replication
- expression of genetic information;
- glial cell proliferation;
- protection against oxidative (oxygen-related) cell damage;
- differentiation of immature neurons;
- death of neurons through apoptosis;
- cytoskeletal dynamics;
- phosphorylation and secretion;
- nerve impulse transmission;
- cell cycle regulation.
Depending on the variety and location, brain-specific s100 proteins can exert both intracellular and extracellular effects. The effect of some proteins is concentration dependent. Thus, the well-known s100B protein exhibits neurotrophic activity at normal contents, and neurotoxic activity at elevated levels.
Extracellular brain-specific s100 proteins can participate in inflammatory reactions, regulate the differentiation of glia and neurons, and also trigger apoptosis (programmed cell death). The importance of s100 was proven in an in vitro experiment in which neurons could not survive without the presence of this protein.
Diagnostic Value s100
The diagnostic value of s100 is based on the relationship of its concentration in blood serum (or cerebrospinal fluid) with CNS pathologies and oncological diseases. It was established that with damage to glial cells, this protein enters the extracellular space, from where it enters the cerebrospinal fluid and then into the blood. Thus, based on an increase in the concentration of s100 in serum, a number of brain pathologies can be concluded. The relationship between the content of this protein in the blood and diseases of the central nervous system has been confirmed experimentally.
An increase in the concentration of s100 in extracellular fluids is caused not only by the destruction of cellular barriers of cells synthesizing this protein. The first reaction to many brain pathologies is the so-called glial response, part of which is an increase in the intensity of s100 secretion by astrocytes. An increase in the content of this protein in the blood may also indicate a violation of the blood-brain barrier.
Monitoring the level of s100 allows you to assess the degree of brain damage, which is of great importance in medical prognosis. The diagnostic relationship between the amount of this protein and neuropathology resembles the correlation of c-reactive protein concentration with systemic inflammation.
Use as a tumor marker
As an tumor marker, s100 protein began to be used in the early 1980s. Currently, this method is effective for the early detection of cancer, relapse or metastasis. Most often, s100 is used in the diagnosis of melanoma or neuroblastoma.
It is necessary to distinguish when the analysis for this protein is carried out to determine pathologies of the central nervous system or other diseases, and when - to detect cancer. If the orientation is aimed specifically at the tumor marker, the decoding of the s100 protein should take into account other possible reasons for the increase in the concentration of the test substance in the blood. When interpreting the results, one must pay attention to the analysis method, since the boundaries of the reference interval (normal indicators) depend on it.
The main disadvantage of the s100 marker is its low selectivity, since an increase in the concentration of this protein in the blood and CSF can be associated with many pathologies, not necessarily of a cancerous nature. Therefore, it is impossible to betray protein s100 determining diagnostic value. Nevertheless, this protein has proven itself as a concomitant oncological marker.
Serum Level
Normally, s100 protein should be present in serum in an amount of less than 0.105 μg / L. This value corresponds to the upper limit of concentration in a healthy person. Exceeding the allowable level (DU) of s100 may indicate:
- Cerebral palsy;
- brain injury;
- the development of malignant melanoma (or its relapse);
- the presence of pregnancy;
- neuroblastoma;
- dermatomyositis;
- covering large areas of burns.
Protein levels can also increase with stress or prolonged exposure to the ultraviolet zone. Blood concentration is determined by appropriate analysis.
Detection in the body
There are several ways to detect the presence of s100 in blood serum, including:
- immunoradiometric analysis (IRMA);
- mass spectroscopy;
- western blot;
- ELISA (enzyme immunoassay);
- electrochemiluminescence;
- quantitative PCR.
All these analytical methods are highly sensitive and allow you to very accurately determine the quantitative content of s100. Since this protein is characterized by a short half-life (30 minutes), a high concentration in serum is possible only with constant intake from the affected tissues.
In clinical diagnostics, automated electrochemiluminescent immunological analysis for s100 protein is most often used. The study combines the use of antibodies to detectable protein with light labeling. The device determines the concentration of s100 by the intensity of chemiluminescent radiation.
Antibodies to protein s100
In medicine, antibodies to the s100 protein have 2 areas of practical application:
- diagnostic - used in immunological methods to detect the concentration of this protein in serum or CSF (in this case, s100 is an antigen);
- therapeutic - the introduction of antibodies into the body is used in the treatment of certain diseases.
Antibodies exert their effect through a modulating effect on s100 proteins. A well-known drug on this basis is Tenoten. Antibodies to s100 have a beneficial effect on the nervous system, improve impulse transmission. In addition, such drugs are able to stop the symptomatic manifestations of disorders of the autonomic function in the digestive system.